Vascular cell adhesion molecule-1 (VCAM-1), a member of the immunoglobulin (Ig) supergene family, is expressed on activated, but not resting, endothelium. The integrin VLA-4 (a4b1), which is expressed on many cell types including circulating lymphocytes, eosinophils, basophils, and monocytes, but not neutrophils, is the principal receptor for VCAM-1. Antibodies to VCAM-1 or VLA-4 can block the adhesion of these mononuclear leukocytes, as well as melanoma cells, to activated endothelium in vitro. Antibodies to either protein have been effective at inhibiting leukocyte infiltration and preventing tissue damage in several animal models of inflammation. Anti-VLA-4 monoclonal antibodies have been shown to block T-cell emigration in adjuvant-induced arthritis, prevent eosinophil accumulation and bronchoconstriction in models of asthma, and reduce paralysis and inhibit monocyte and lymphocyte infiltration in experimental autoimmune encephalitis (EAE). Anti-VCAM-1 monoclonal antibodies have been shown to prolong the survival time of cardiac allografts. Recent studies have demonstrated that anti-VLA-4 mAbs can prevent insulitis and diabetes in non-obese diabetic mice, and significantly attenuate inflammation in the cotton-top tamarin model of colitis.
Thus, compounds which inhibit the interaction between xcex14-containing integrins, such as VLA-4, and VCAM-1 are useful as therapeutic agents for the treatment of inflammation caused by chronic inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), pulmonary inflammation (e.g., asthma), and inflammatory bowel disease (IBD).
These applications disclose the acids and esters corresponding to the alcohol compounds of this invention and the method of preparing these acids and esters. The disclosure of these U.S. patent applications are hereby incorporated by reference.
It has been discovered that compounds of the formula: 
and the pharmaceutically acceptable salts and esters thereof wherein X and Y are as defined below, are more readily absorbed and more bioavailable than the corresponding carboxylic acids from which they are derived, both of which are effective inhibitors of the binding of VCAM-1 to VLA-4 in vivo and are useful in treating inflammation in inflammatory diseases in which such binding acts to bring on the inflammation.